One of the key goals in many clinical interventions is to be able to modulate brain's activity as needed. In some circumstances such as neurodegenerative diseases, one often aims to enhance the brain activity. In other cases such as epileptic seizure, one wishes to decrease the brain activity. Existing approaches include surgical procedures, transcranial stimulation, and pharmacological treatment. However, these approaches have their respective limitations. It would be of great interest to develop a non-invasive, convenient and cost- effective means to modulate brain activity. The overarching goal of the present project is to establish that control of the inspired air can be used as a simple maneuver to modulate brain activity in a quantitative manner. We will used several advanced Magnetic Resonance Imaging (MRI) techniques (some developed by the Principal Investigator) to study the effects of CO2 and O2 inspiration on neural activity and metabolism. As a proof-of-principle for potential clinical utility, we will also test whether 5% CO2 inhalation can reduce seizure activities in patients with epilepsy. The specific aims of the proposal are: 1: To compare cerebral metabolic rate of oxygen, CMRO2, between normocapnia and graded hypercapnia conditions. 2a. To investigate CO2- induced changes in brain's arousal state using electroencephalography (EEG). 2b. To investigate CO2- induced changes in spontaneous brain activity at rest, as assessed by cross-correlation coefficient (cc) in functional connectivity MRI (fcMRI). 3. To measure CMRO2 and spontaneous brain activity under different levels of O2-breathing conditions. 4. To compare the extent of epileptic seizure activity during normocapnia and hypercapnia states in a patient group. Understanding how the inspired gas content changes neural activity will provide a better understanding of neural and metabolic regulation in the brain, improve the interpretation of several functional brain mapping techniques, and may also lay a foundation for exploring gas-based intervention in epilepsy when conventional drugs are not effective. PUBLIC HEALTH RELEVANCE: Clinical interventions of brain diseases often require the ability to change brain's activity as needed. In this project, a new approach to change brain activity will be tested in which the content of the inspired air is modulated. This approach is non-invasive, convenient and cost effective, thus may provide a new means for interventions such as seizure termination in epilepsy patients.